Over 30 million people are currently infected by HIV and over two thirds of them currently reside in sub- Saharan Africa. There are still over 2 million new infections occurring annually in spite of numerous prevention programs. Of the new infections, the fastest growing and most rapidly spreading subtype is HIV-1 subtype C. This subtype is most prevalent in regions such as Asia and Africa where a preponderance of poverty and high HIV infection rates co-exist. There are now growing evidence that there are differences among different subtypes, such as subtype C, in disease manifestation and pathogenesis. However, little is known about the neurological manifestation, neuropathogenesis, and neuroinvasiveness of subtype C HIV-1, and whether the central nervous system can be a sanctuary for subtype C HIV-1 is not known. Preliminary data derived from our recent R21 pilot project to study subtype C HIV/AIDS neuropathogenesis in Zambia have shown that neurocognitive impairment in motor functions and certain behavioral tasks could be reversed by anti-retroviral therapy (ART). There were substantial levels of meningitis, lymphocyte infiltration and neuroinflammation. A high frequency of opportunistic infection, especially mycobacterium tuberculosis, was detected. Therefore, the effects of subtype C HIV-1 infection at the neurohistopathological level needs to be further investigated. The overall goal of this proposal is to determine the effects and possible mechanism of HIV-1 subtype C neuropathogenesis and viral invasiveness, and the effect of ART. This will be accomplished with three specific aims: 1) To determine whether neuropathogenesis and viral neuroivasiveness are related to the AIDS disease progression in a predominately subtype C HIV-1 population; 2) To determine the role of opportunistic infection and HIV-1 in the development of neuropathology and their correlation with HIV disease progression; 3) To determine the effect of ART on subtype C HIV associated neuropathology, HIV viral load and whether the brain can serve as a reservoir for viral compartmentalization and persistent infection. Given the predominance of subtype C HIV infection and the scale up of anti-viral therapy globally, a better understanding of subtype C HIV neuropathogenesis will have substantial impact on both disease management and the use of anti-retroviral therapy in infected individuals, especially when the effects of ART on subtype C HIV infection and drug resistance is not fully understood. Our study will also lead to better treatment regimens, interventions, and will lead to the development of novel preventive strategies.